Nicotine-addled memories feed the addiction

Smoking can be a hard habit to break. New research shows how nicotine hijacks …

Every year, millions of smokers struggle and ultimately fail to break their addiction to nicotine. Of the almost 35 million smokers who try to quit, over 85 percent eventually relapse—typically within a week—according to the National Institute on Drug Abuse. It’s not hard to see why.

Nicotine is notoriously effective at activating the central nervous system's reward circuits, flooding them with pleasure-enhancing dopamine, and smoking provides the quickest route for it to permeate the brain. Like other addictive substances, it can influence synaptic potentiation—the strengthening of neural connections that occurs during learning and memory formation—through dopamine signaling. The release of dopamine in the hippocampus induces memory formation by establishing a connection between the brain’s reward pathways and its memory systems. This form of associative memory can perpetuate addiction by linking pleasant memories to drug use.

Jianrong Tang and John Dani of the Baylor College of Medicine, Houston, suspected that nicotine was hijacking these pathways in order to trigger addiction. Several studies had already shown that nicotine could influence synaptic potentiation, but they had been compromised by the use of deep urethane anesthesia, a technique that changes ligand-gated channels in the brain, and high doses of nicotine. Tang and Dani decided to monitor the induction of synaptic potentiation in mice that were given biologically relevant doses of nicotine. Their results appear in Neuron.

At the beginning of the experiment, electrodes were surgically implanted in the dentate gyrus (a region of the hippocampus) of the mice to track the neural activity associated with synaptic potentiation. The dentate gyrus houses the medial perforant path, which carries contextual, spatial, and temporal information from the neocortex to the hippocampus. The absorption of nicotine produces a distinct peak, called a pop (short for population) spike that can be easily identified.

After giving the mice 2 weeks to become habituated to the electrodes, Tang and Dani injected them with increasing amounts of nicotine (0.1, 0.5, 1.0 mg/kg) or a saline control, over a 4-day period. Of the 4 treatments, only the 2 higher nicotine concentrations induced synaptic potentiation. This effect lasted several hours—over 5 hours when 1 mg/kg was administered, far outstripping the half life of nicotine in mice, which is 5-8 minutes.

Thus, the continued presence of nicotine did not seem necessary for synaptic enhancement to occur. The authors also found that the potentiation effect was not due to an increase in the number of afferent axons, which carry the nerve impulses from nicotine receptors to the brain.

Next, they systematically blocked several dopamine receptors within the dentate gyrus in order to inhibit nicotine-induced potentiation. The results indicated that a dopamine signal acting locally within the hippocampus is required for potentiation to occur. Moreover, the magnitude of the induced potentiation was directly related to the strength of the signal.

Dopamine signaling also enabled conditioned place preference (CPP), the mechanism responsible for creating an association between an environment and a reward, in mice injected with the 0.5 mg/kg dose. (The highest concentration acted as a mild sedative, rendering the mice practically immobile and slowing potentiation.)

Taken together, these results suggest the existence of a direct link between nicotine use and memory formation: the more one smoked, the stronger the dopamine signal and, thus, the stronger synaptic potentiation became. As a result, the memories induced by chronic nicotine use perpetuate addiction. As the authors put it: "Environmental cues previously associated with drug use elicit internal sensation-based memories that motivate the desire for the drug, making long-term abstinence difficult.”

These findings are consistent with others that show that nicotine improves attention and memory in both mice and humans. A study published in August found that nicotine use greatly improved brain function in schizophrenics, allowing them to stay focused and to think more clearly. This has led some to argue that nicotine-based drugs, or drugs that target nicotine receptors, could be used to treat cognitively impaired patients. This latest study may help researchers better understand the underlying mechanisms of addiction for other drugs and eventually design more effective treatments to prevent relapse.